Human equilibrative nucleoside transporter 1 (hENT1) expression is a potential predictive tool for response to gemcitabine in patients with advanced cholangiocarcinoma
Introduction
Cholangiocarcinoma (CC) is the second most frequent primary cancer of the liver. Worldwide, CC accounts for 3% of all gastrointestinal cancers. Its incidence has been rising over the past two decades in the United States and France.1, 2 It arises from the epithelial lining of the intrahepatic or extrahepatic bile duct. The anatomic location of CC can be described as intrahepatic, perihilar or distal extrahepatic. Five year survival rates are around 10–40% for CC.3 Complete surgical resection offers the only chance for cure. However, only 10–20% of patients present with early stage disease are considered surgical candidates. Among these resected patients, recurrence rates are high, thus for the vast majority of CC patients, systemic chemotherapy is the mainstay of their treatment plan. Patients with unresectable or metastatic CC have a poor prognosis with a median overall survival (OS) of <1 year, as shown by a comprehensive pooled analysis of published clinical trials.4 These authors also showed that chemotherapy with gemcitabine combined with cisplatin or oxaliplatin could increase response rate and tumour control rate in CC. Very recently, a randomised controlled phase III study, the ABC-02 study5, has shown a clear benefit of a combination regimen over gemcitabine alone, considered by many as the standard chemotherapy. Authors show the superiority of the combination of cisplatin and gemcitabine over gemcitabine alone, in terms of Progression Free Survival (PFS) and OS, with a nearly 4 month absolute benefit in survival and a hazard ratio of death of 0.63 (p < 0.0001). This combination can thus be considered the new standard for advanced non-operable or metastatic CC.
However, chemotherapy is administered to patients without knowledge of the genetic background of the disease, which may affect drug efficacy.
Genetically determined variability of key enzymes has been shown to influence response and toxicity of cytotoxic agents including 5-fluorouracil, irinotecan and 6-mercaptopurine.6 Potential candidates to predict which patients are likely to respond to treatment are genes encoding proteins involved in metabolism, transport across membranes, or target of anticancer drugs.7 It is likely that genetic variability of key enzymes in gemcitabine transport and metabolism may therefore have an impact on treatment response and toxicity of gemcitabine. Because the biochemical targets of gemcitabine are intracellular, the mandatory first step in the production of cytotoxicity is permeation across the cell membrane. Gemcitabine and physiologic nucleosides are hydrophilic, and diffusion through the cell membrane lipid layer is slow. Therefore, efficient cellular uptake requires the presence of specialised integral membrane nucleoside transporter proteins.8 Two general processes of nucleoside transport have been identified: the equilibrative bi-directional facilitators (human equilibrative nucleoside transporter 1) and the concentrative sodium/nucleoside symporters (hCNT1 and 3). The major routes for transporting gemcitabine are human equilibrative nucleoside transporter (hENT1) and to lesser extent, hCNT1 and hCNT3.9, 10, 11 Authors have shown that cells lacking hENT1 are highly resistant to gemcitabine.12 The abundance and distribution of the hENT1 protein can be evaluated using immunohistochemistry and has been assessed in a number of malignant and benign tissues.13, 14, 15, 16, 17 Very interestingly, a recent randomised phase III trial showed that hENT1 protein expression was associated with an increased overall and disease-free survival in patients operated for a pancreatic cancer who received adjuvant gemcitabine, but not in those who received 5-FU and radiotherapy after surgery, suggesting that hENT1 expression may be predictive of response to gemcitabine.18 These results have been reproduced by others.19
On the other hand, two retrospective studies showed that overexpression of hENT1 protein was significantly correlated with poor prognosis in patients with resected ampullary and gastric cancers that did not receive any chemotherapy,13, 17 suggesting that hENT1 expression could also be a prognostic marker.
On the basis of these findings, we reviewed the files of 43 patients treated at our centre with a locally advanced or metastatic CC, out of 60 patients who received first line treatment with gemcitabine alone. The aim of the study was to determine whether there was a correlation between the expression of hENT1 and disease outcomes in CC. We excluded 17 patients treated with gemcitabine for a gallbladder cancer, because their prognosis and sensitivity to chemotherapy is different.4 Although increasing knowledge suggests that extrahepatic (including perihilar) CC and intrahepatic CC could have different pathophysiology, they share common molecular features, as described by a recent review,20 and are treated the same way. We therefore decided to analyse together both extra- and intrahepatic CC in this study.
Section snippets
Clinical data and tumour specimen acquisition
This retrospective study was restricted to patients with a CC, excluding gallbladder and ampullary cancer, followed-up and treated with gemcitabine as first-line therapy, at the Cliniques universitaires Saint-Luc, Université catholique de Louvain in Bruxelles, between July 1998 and November 2007. Data on clinical variables, including sex, age, and TNM classification were gathered from patient record files. Tumour samples were obtained from surgery blocks (23% of patients had prior surgery) or
Patient population
The main patients’ characteristics are summarised in Table 1. The cohort consisted of 43 patients (20 males), with pathology-proven diagnosis of a locally advanced (i.e. deemed unresectable) or metastatic CC. The median age at diagnosis was 62 years (range 43–80). Seventeen patients had an extrahepatic CC (Klatskin and distal tumours), 26 having an intrahepatic tumour; 29 had metastatic disease at the time of initiation of the treatment with gemcitabine. Twelve patients (28%) had had prior
Discussion
In this study, we analysed the potential role of hENT1 expression as a predictive marker of gemcitabine efficacy given as first-line exclusive therapy to patients with advanced CC, excluding gallbladder cancer. Our findings support the assumption that high expression of hENT1 confers an increase both in PFS and OS to these patients. These findings were made both in univariate and multivariate analysis, after adjustment for standard clinicopathologic prognostic factors. There is a substantial
Conflict of interest statement
None declared.
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2019, Critical Reviews in Oncology/HematologyCitation Excerpt :One study Woo et al. (2017) did not report the cut-off value. Of the 8 studies that evaluated the correlation between hENT1 expression and survival in BTC patients treated with gemcitabine or gemcitabine-based chemotherapy, 6 studies reported OS (Santini et al., 2011; Deng et al., 2014; Murata et al., 2013; Borbath et al., 2012; Kobayashi et al., 2012; Sasaki et al., 2014) and DFS or PFS (Santini et al., 2011; Woo et al., 2017; Deng et al., 2014; Borbath et al., 2012; Brandi et al., 2016; Sasaki et al., 2014) (Table 1 and 2). All 6 studies found a prolonged OS in patients with high levels of hENT1 compared to patients with low hENT1 expression, and this difference in OS was statistically significant in 5 of 6 studies.
Outcomes of adjuvant treatments for resectable intrahepatic cholangiocarcinoma: Chemotherapy alone, sequential chemoradiotherapy, or concurrent chemoradiotherapy
2018, Radiotherapy and OncologyCitation Excerpt :The conclusions of the current study could not be overturned, even relatively advanced pathologic stages and margin-positive resected ICC in adjuvant CCRT group. Sixth, levels of hENT-1, the major intracellular transporter of gemcitabine [58–61] and a predictive biomarker of response to gemcitabine, were not recorded in the current data, although only 10% of patients received gemcitabine in our study. Therefore, to obtain crucial information on population specificity and disease occurrence, a large-scale randomized trial comparing carefully selected patients undergoing suitable treatments is essential.
Molecular bases of the poor response of liver cancer to chemotherapy
2018, Clinics and Research in Hepatology and GastroenterologyCitation Excerpt :It would be interesting to confirm whether, similarly to HCC [14], these changes could be related with the outcome of CCA patients treated with sorafenib. Since nucleoside transporters (CNTs and ENTs, SLC28 and SLC29 families) are involved in gemcitabine uptake [91], their expression, mainly that of ENT1, can predict the response to this drug in CCA patients [92]. Down-regulation in CCA of the copper transporter CTR1 (SLC31A1), able to transport platinum derivatives, has been reported [3].